Pyrrole positional selectivity

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

This low substrate selectivity and the low positional selectivity (see Section III,B) are in keeping with a transition state little perturbed with respect to the initial state. This was to be expected, on the basis of the Hammond postulate,183 in view of the very great reactivity of the pyrrole ring. 

Indole (2) undergoes electrophilic substitution preferentially at the b(C3)-position whereas pyrrole (1) reacts predominantly at the a(C2)-position [15]. The positional selectivity in these five-membered ring systems is well explained by the stability of the Wheland intermediates for electrophilic substitution. The intermediate cations from 3 (for indole, 2) and a (for pyrrole, 1) are the more stabilized. Pyrrole compounds can also participate in cycloaddition (Diels-Alder) reactions under certain conditions, such as Lewis acid catalysis, heating, or high pressure [15]. However, calculations of the frontier electron population for indole and pyrrole show that the HOMO of indole exhibits high electron density at the C3 while the HOMO of pyrrole is high at the C2 position [25-28] (Scheme 3). 

L. I. Belen kii, I. A. Suslov, N. D. Chuvylkin, Substrate and Positional Selectivity in Electrophilic Substitution Reactions of Pyrrole, Furan, Thiophene, and Selenophene Derivatives, Chem. Heterocycl. Compd. 2003, 39, 36- 8. 

Figure 12. Trace A 1H NMR spectrum of the porphyrin x-radical generated from (N -MeTTP)FenCl and excess m-CPBA (denoted 5 in this figure) at —90 °C in CD2Cl2. Trace B 2H NMR spectrum of 5 selectively deuterated at the meso-phenyl positions. Trace C 2H NMR spectrum of 5 selectively deuterated at the /3-pyrrole positions. (Reproduced with permission from reference 52. Copyright 1990.)...

Quantum chemical study of positional selectivities in reactions of furan, thiophene, selenophene, N-unsubstituted pyrrole and related benzannulated systems with electrophiles... 

Quantum chemical study of positional selectivity in reactions of N-substituted pyrroles with electrophiles 169... 

Electrophilic substitution is an important type of reactions for five-membered heterocycles with one heteroatom and enables compounds with various substituents to be obtained. The present work is devoted to certain features of substrate and positional selectivities in electrophilic substitution reactions of derivatives of pyrrole, furan, thiophene and selenophene, and also the corresponding benzannulated systems, which had not been explained until recently. In a recent review (05RKZ(6)59), these problems were mainly discussed for thiophenes, while in a previous review (94H(37)2029) only monocyclic pyrrole, furan and thiophene derivatives were considered. 

POSITIONAL SELECTIVITY IN REACTIONS OF FURAN, THIOPHENE, SELENOPHENE, PYRROLE AND THEIR DERIVATIVES WITH ELECTROPHILES... 

The data considered confirm the reactivity sequence pyrrole furan > selenophene > thiophene for substrate selectivity on electrophilic substitution (71 AHC(13)235) and show that the positional selectivity is reduced in the series furan > selenophene > thiophene > pyrrole, which correlate with that for the relative stability of the onium states of the elements (O < Se < S " < N" ") in agreement with the hypothesis proposed previously (79MI2,80KGS1587), not including selenophene and its derivatives. 

We undertook a quantum chemical study of the protonation of monocyclic and benzannulated five-membered heterocyclic systems with one heteroatom (03KGS38). The initial calculations, carried out by the semi-empirical CNDO/2 method (81ZOR1129), gave values for the differences in energy of the cations formed on protonation of the a- and yS-positions iAEa-p) that corresponded with the available experimental data on the sequence of change in positional selectivity furan > thiophene > pyrrole. However, the place of selenophene between thiophene and pyrrole in this series predicted by these calculations was contradicted by the experimental results obtained later (95JHC53). The results of calculations by the MNDO and PM3 methods also did not fit the experimental data, possibly linked with poor parametrization for selenium atom (97M12). 

Structural changes affect seriously an electrophilic substitution orientation in pyrroles owing to their low positional selectivity in reactions with electrophiles. Thus, in contrast to thiophene, selenophene, and, especially, furan analogues, even a relatively weak type 11 substituent in position 2 of the pyrrole ring is capable of overcoming the a-oiienting effect of the heteroatom and directs an electrophile preferably to the position 4 (68JCS(B)392). N-(p-Nitrophenyl)pyrrole-2-carbaldehyde... 

The positional selectivity on alkylation of N-(phenylsulfonyl)pyrrole in the presence of AICI3 changes from preferential a-substitution (with EtBr), through the formation of 1 1 mixture of a- and jS-substituted derivatives (with i-PrCl), to preferential (80%) formation of the jS-substituted derivative in the case of f-BuCl (85CJC896). 

Substituents in the pyrrole ring affected drastically the ratio of pyrrole-1- to pyrrole-2-carbodithioate isomers. With unsubstituted pyrrole, only the 1-isomer 135 (R = R = R = H, R = Et) was formed (63%) and practically no 2-isomer was detected. When just one methyl group was introduced into pyrrole s a-position, the pyrrole-2-carbo-dithioates 134 became the only product (46%) (Equation (38)). Any combinations of alkyl substituents on the pyrrole ring selectively gave pyrrole-2-carbodithioates 134 in a yield of up to 71%. With an aryl substituent at the a-position, along with the major pyrrole-2-carbodithio-ates 134 (44-59%), the 1-isomers 135 were also formed in 24—33% yields (Equation (38)). 

Fig. 32. Positional selectivity of gaseous CH3FCH3 and ions toward pyrroles...

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

The positional selectivity of attack on pyrroles can be completely altered by the presence of bulky gronps on nitrogen l-(t-butyldimethylsilyl)pyrrole and l-(tri-i-propylsilyl)pyrrole are attacked exclusively at their P-positions. ... 

Positional selectivity in these five-membered systems, and their high reactivity to electrophitic attack, are well explained by a consideration of the Wheland intermediates (and by implication, the transition states that lead to them) for electrophilic substitution. Intermediate cations from both a- and P-attack are stabilised (shown for attack on pyrrole). The delocalisation, involving donation of electron density from the heteroatom, is greater in the intermediate from a-attack, as illustrated by the number of low-energy resonance contributors. Note that the C-C double bond in the intermediate for p-attack is not and cannot become involved in delocalisation of the charge. 

Kinetic studies of acylation reactions are somewhat limited by the insolubility of the acyl halide-Lewis acid complexes in many of the solvent systems that are used. However, useful results have been obtained and, as far as we are concerned, relative rates of reactions are of greater importance than absolute values. In any case it is not possible to distinguish between the two mechanistic extremes on the basis of the observed kinetics." Friedel-Crafts acylations are generally characterized by high substrate selectivity and frequently by high positional selectivity. Relative rate data show, as expected, that toluene is more reactive than benzene and that /n-xylene is the most reactive of the dimethylbenzenes. Values, relative to benzene, for benzoylation catalyzed by aluminum chloride were r-butylbenzene (72), toluene (1.1 X 10 ), p-xylene (1.4 x 10 ), o-xylene (1.12 x 10 ), and m-xylene (3.94 x 10- ). Competition data for the trifluoroacetylation of a number of heterocycles using trifluoroacetic anhydride at 75 "C gave the relative rates thiophene (1.0), furan (1.4 x lO ), 2-methylfuran (1.2 x 10 ) and pyrrole (5.3 x 10 ). ... 

Electrophilic reactions on the electron-rich, aromatic thiophene nucleus continue to provide a powerful route to substituted derivatives. Comparison of positional selectivity of the heteroarenium ions derived from furan. pyrrole or thiophene suggest that ease of P-substitution correlates with the relative stabilities <94H2029>. Freidel-Crafts reaction of 2,5-... 

In 2002 Sessler et al. designed two cytosine-substituted calix[4]pyrrole conjugates with a cytosine moiety attached either at a p- or meso-pyrrolic position (43 and 44, Fig. 24.18). These hetero-calix[4]arene nucleobase conjugates were tested as nucleotide-selective carriers and as active components of nucleotide-sensing ion-selective electrodes [52]. 

A DFT study has been reported regarding the positional selectivity to electrophilic attack in five-membered heterocycles including A-substituted pyrroles. The regiospe-cific alkylation of pyridyl alcohols has been achieved by reaction with alkyl lithium... 

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